Identification of a Novel Cell Death Receptor Mediating IGFBP-3-induced Anti-tumor Effects in Breast and Prostate Cancer

• Published in: The Journal of biological chemistry 2010-09, Vol.285 (39), p.30233-30246
• Main Authors: Ingermann, Angela R., Yang, Yong-Feng, Han, Jinfeng, Mikami, Aki, Garza, Amanda E., Mohanraj, Lathika, Fan, Lingbo, Idowu, Michael, Ware, Joy L., Kim, Ho-Seong, Lee, Dae-Yeol, Oh, Youngman
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Base Sequence; Breast Cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Caspase; Caspase 8 - genetics; Caspase 8 - metabolism; Cell Biology; Cell Line, Tumor; Death Receptor; Female; Gene Expression Regulation, Neoplastic - genetics; Gene Knockdown Techniques; Humans; IGFBP-3 Receptor; Insulin-like Growth Factor (IGF); Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor Binding Proteins - genetics; Insulin-Like Growth Factor Binding Proteins - metabolism; Male; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Nude; Molecular Sequence Data; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasm Transplantation; Prostate Cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptors; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Signal Transduction; Transplantation, Heterologous; Tumor Suppressor
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.122226

Insulin-like growth factor-binding protein-3 (IGFBP-3), a major regulator of endocrine actions of IGFs, is a p53-regulated potent apoptotic factor and is significantly suppressed in a variety of cancers. Recent epidemiologic studies suggest that IGFBP-3 contributes to cancer risk protection in a variety of cancers, and a polymorphic variation of IGFBP-3 influences cancer risk, although other studies vary in their conclusions. Some antiproliferative actions of IGFBP-3 have been reported to be independent of IGFs, but the precise biochemical/molecular mechanisms of IGF-independent, antiproliferative actions of IGFBP-3 are largely unknown. Here we report a new cell death receptor, IGFBP-3R, that is a single-span membrane protein and binds specifically to IGFBP-3 but not other IGFBP species. Expression analysis of IGFBP-3 and IGFBP-3R indicates that the IGFBP-3/IGFBP-3R axis is impaired in breast and prostate cancer. We also provide evidence for anti-tumor effect of IGFBP-3R in vivo using prostate and breast cancer xenografts in athymic nude mice. Further in vitro studies demonstrate that IGFBP-3R mediates IGFBP-3-induced caspase-8-dependent apoptosis in various cancer cells. Knockdown of IGFBP-3R attenuated IGFBP-3-induced caspase activities and apoptosis, whereas overexpression of IGFBP-3R enhanced IGFBP-3 biological effects. IGFBP-3R physically interacts and activates caspase-8, and knockdown of caspase-8 expression or activity inhibited IGFBP-3/IGFBP-3R-induced apoptosis. Here, we propose that IGFBP-3R represents a novel cell death receptor and is essential for the IGFBP-3-induced apoptosis and tumor suppression. Thus, the IGFBP-3/IGFBP-3R axis may provide therapeutic and prognostic value for the treatment of cancer.